Regulation of the Pannexin-1 Promoter in the Rat Epididymis1

Dufresne, Julie; Cyr, Daniel G.

doi:10.1095/biolreprod.114.122168

Cited by 16 publications

(20 citation statements)

References 65 publications

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“…To explore the functionality of Panx1 channels in adipocytes we performed experiments with cultured 3T3-L1 adipocytes and primary adipocytes isolated from wild-type or Panx1 KO mice, using known activators of Panx1 channel function [28,30,32] . We found that Panx1 expression in 3T3-L1 adipocytes is induced by insulin ( Figure S1B ), which is in line with reports that cAMP response elements play a role in transcriptional regulation of Panx1 [46] . First indications for a functional role of Panx1 in adipocytes came from experiments where treatment of 3T3-L1 adipocytes with the α-adrenergic receptor agonist phenylephrine (PE) caused a dose-dependent increase in the uptake of YO-PRO ® , a green-fluorescent dye that can enter cells via open Panx1 channels [28,47] ( Figure 1 A).…”

Section: Resultssupporting

confidence: 91%

Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes

Adamson

Meher

Chiu

et al. 2015

Molecular Metabolism

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ObjectiveDefective glucose uptake in adipocytes leads to impaired metabolic homeostasis and insulin resistance, hallmarks of type 2 diabetes. Extracellular ATP-derived nucleotides and nucleosides are important regulators of adipocyte function, but the pathway for controlled ATP release from adipocytes is unknown. Here, we investigated whether Pannexin 1 (Panx1) channels control ATP release from adipocytes and contribute to metabolic homeostasis.MethodsWe assessed Panx1 functionality in cultured 3T3-L1 adipocytes and in adipocytes isolated from murine white adipose tissue by measuring ATP release in response to known activators of Panx1 channels. Glucose uptake in cultured 3T3-L1 adipocytes was measured in the presence of Panx1 pharmacologic inhibitors and in adipocytes isolated from white adipose tissue from wildtype (WT) or adipocyte-specific Panx1 knockout (AdipPanx1 KO) mice generated in our laboratory. We performed in vivo glucose uptake studies in chow fed WT and AdipPanx1 KO mice and assessed insulin resistance in WT and AdipPanx1 KO mice fed a high fat diet for 12 weeks. Panx1 channel function was assessed in response to insulin by performing electrophysiologic recordings in a heterologous expression system. Finally, we measured Panx1 mRNA in human visceral adipose tissue samples by qRT-PCR and compared expression levels with glucose levels and HOMA-IR measurements in patients.ResultsOur data show that adipocytes express functional Pannexin 1 (Panx1) channels that can be activated to release ATP. Pharmacologic inhibition or selective genetic deletion of Panx1 from adipocytes decreased insulin-induced glucose uptake in vitro and in vivo and exacerbated diet-induced insulin resistance in mice. Further, we identify insulin as a novel activator of Panx1 channels. In obese humans Panx1 expression in adipose tissue is increased and correlates with the degree of insulin resistance.ConclusionsWe show that Panx1 channel activity regulates insulin-stimulated glucose uptake in adipocytes and thus contributes to control of metabolic homeostasis.

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Section: Resultssupporting

confidence: 91%

Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes

Adamson

Meher

Chiu

et al. 2015

Molecular Metabolism

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“…and reverse primer, one of them being biotinylated (49). Information about PCR and sequencing primers and the sequence-to-analyze is summarized in Table 1 (11). Quantification of the DNA methylation status of the Panx1 was performed on a PyromarkQ24 system (Qiagen) as described by Freitag et al (15).…”

Section: Methodsmentioning

confidence: 99%

Parental vitamin D deficiency during pregnancy is associated with increased blood pressure in offspring viaPanx1hypermethylation

Meems

Mahmud

Buikema

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Vitamin D deficiency is one of the most common nutritional deficiencies worldwide. Maternal vitamin D deficiency is associated with increased susceptibility to hypertension in offspring, but the reasons for this remain unknown. The aim of this study was to determine if parental vitamin D deficiency leads to altered DNA methylation in offspring that may relate to hypertension. Male and female Sprague-Dawley rats were fed a standard or vitamin D-depleted diet. After 10 wk, nonsibling rats were mated. The conceived pups received standard chow. We observed an increased systolic and diastolic blood pressure in the offspring from depleted parents (F1-depl). Genome-wide methylation analyses in offspring identified hypermethylation of the promoter region of the Pannexin-1 (Panx1) gene in F1-depl rats. Panx1 encodes a hemichannel known to be involved in endothelial-dependent relaxation, and we demonstrated that in F1-depl rats the increase in blood pressure was associated with impaired endothelial relaxation of the large vessels, suggesting an underlying biological mechanism of increased blood pressure in children from parents with vitamin deficiency. Parental vitamin D deficiency is associated with epigenetic changes and increased blood pressure levels in offspring.

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“…Jiang et al reported increases in expression of Panx1 in mouse models of inducible stroke, which are associated with increased TNF-induced inflammation and tissue injury (Bokhari et al, 2014; Jiang et al, 2012; Liu and McCullough, 2011; Tuttolomondo et al, 2009; Tuttolomondo et al, 2014). In silico analysis has highlighted a number of transcriptional start sites within the rat Panx1 sequence, with binding sites for several transcription factors including CREB and ETV4 as well as factors downstream from IL-6 that have been identified (Dufresne and Cyr, 2014). Our RNA-seq data highlighted that TNF upregulates all NFκβ genes in HUVECs.…”

Section: Discussionmentioning

confidence: 99%

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Yang

DeLalio

Best

et al. 2019

Preprint

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25inflammation, endothelial cell, smooth muscle cell 4 to prolonged tumor necrosis factor alpha (TNF) treatment, Yang et al. found that the Panx1 5 channel is targeted to the plasma membrane, where it facilitates an increase in intracellular 6 calcium to control the production and release of cytokines including IL-1β. 7 8 GRAPHICAL ABSTRACT 9 10 Graphical Abstract: The inflammatory process in endothelial cells is controlled by Ca 2+ entry through Pannexin 1 membrane channels. 3 Abstract 1The proinflammatory cytokine IL-1β is a significant risk factor in cardiovascular disease 2 that can be targeted to reduce major cardiovascular events. IL-1β expression and release 3 are tightly controlled by changes in intracellular Ca 2+ . In addition, purinergic signaling 4 through ATP release has also been reported to promote IL-1β production. Despite this, 5 the mechanisms that control IL-1β synthesis and expression have not been identified. 6The pannexin 1 (Panx1) channel has canonically been implicated in ATP release, 7 especially during inflammation. However, resolution of purinergic signaling occurs quickly 8 due to blood flow and the presence of ectonucleotidases. We examined Panx1 in human 9 endothelial cells following treatment with the pro-inflammatory cytokine tumor necrosis 10 alpha (TNF). In response to long-term TNF treatment, we identified a dramatic increase 11 in Panx1 protein expression at the plasma membrane. Analysis by whole transcriptome 12 sequencing (RNA-seq), qPCR, and treatment with specific kinase inhibitors, revealed that 13 TNF signaling induced NFκβ-associated Panx1 transcription. Genetic inhibition of Panx1 14 reduced the expression and secretion of IL-1β. We initially hypothesized that increased 15Panx1-mediated ATP release acted in a paracrine fashion to control cytokine expression. 16However, our data demonstrate that IL1-β expression was not altered after direct ATP 17 stimulation, following degradation of ATP by apyrase, or after pharmacological blockade 18 of P2 receptors. These data suggest that non-purinergic pathways, involving Panx1, 19 control IL-1β production. Because Panx1 forms a large pore channel, we hypothesized it 20 may act to passively diffuse Ca 2+ into the cell upon opening to regulate IL-1β. High-21 throughput flow cytometric analysis demonstrated that TNF treatments lead to elevated 22 intracellular Ca 2+ . Genetic or pharmacological inhibition of Panx1 reduced TNF-23 associated increases in intracellular Ca 2+ , and IL-1β transcription. Furthermore, we found 24 that the Ca 2+ -sensitive NFκβ-p65 protein failed to localize to the nucleus after genetic or 25 pharmacological block of Panx1. Taken together, our study provides the first evidence 26 that intracellular Ca 2+ regulation via the Panx1 channel induces a feed-forward effect on 27NFκβ to regulate IL-1β synthesis and release in endothelium during inflammation. 28 4 (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates

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Regulation of the Pannexin-1 Promoter in the Rat Epididymis1

Cited by 16 publications

References 65 publications

Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes

Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes

Parental vitamin D deficiency during pregnancy is associated with increased blood pressure in offspring viaPanx1hypermethylation

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

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